The Journal of Neuroscience, November 11, 2009 • 29(45):14265–14270 • 14265
Brief Communications
Why Sex Matters: Brain Size Independent Differences in
Gray Matter Distributions between Men and Women
Eileen Luders,1 Christian Gaser,2 Katherine L. Narr,1 and Arthur W. Toga1
Laboratory of Neuro Imaging, Department of Neurology, School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-7334,
and 2Department of Psychiatry, University of Jena, 07740 Jena, Germany
1
The different brain anatomy of men and women is both a classic and continuing topic of major interest. Among the most replicated and
robust sex differences are larger overall brain dimensions in men, and relative increases of global and regional gray matter (GM) in
women. However, the question remains whether sex-typical differences in brain size (i.e., larger male and smaller female brains) or
biological sex itself account for the observed sex effects on tissue amount and distribution. Exploring cerebral structures in men and
women with similar brain size may clarify the true contribution of biological sex. We thus examined a sample of 24 male and 24 female
subjects with brains identical in size, in addition to 24 male and 24 female subjects with considerable brain size differences. Using this
large set of brains (n ! 96), we applied a well validated and automated voxel-based approach to examine regional volumes of GM. While
we revealed significant main effects of sex, there were no significant effects of brain size (and no significant interactions between sex and
brain size). When conducting post hoc tests, we revealed a number of regions where women had larger GM volumes than men. Importantly, these sex effects remained evident when comparing men and women with the same brain size. Altogether, our findings suggest that
the observed increased regional GM volumes in female brains constitute sex-dependent redistributions of tissue volume, rather than
individual adjustments attributable to brain size.
Introduction
Although there are many similarities in male and female brains,
there are also various neuroanatomical features that differ between men and women (Cosgrove et al., 2007). Among the most
replicated sexually dimorphic characteristics are larger overall
brain sizes in men and larger global gray matter (GM) proportions as well as regional GM volumes and concentrations in
women (Schlaepfer et al., 1995; Gur et al., 1999; Nopoulos et al.,
2000; Good et al., 2001; Luders et al., 2005; Leonard et al., 2008).
Similarly, larger measurements in women than in men have been
reported with respect to cortical thickness (Narr et al., 2005; Im et
al., 2006; Luders et al., 2006a), cortical convolution (Luders et al.,
2004, 2006b), and the dimensions of predefined regions (Filipek
et al., 1994; Giedd et al., 1996; Harasty et al., 1997; Goldstein et al.,
2001; Rademacher et al., 2001). While some of these prior studies
Received May 13, 2009; revised Sept. 1, 2009; accepted Sept. 3, 2009.
This work was supported by the National Institutes of Health (NIH) through the NIH Roadmap for Medical
Research, Grant U54 RR021813 entitled Center for Computational Biology. Additional support was provided by NIH
(P41 RR013642 and M01 RR000865), by the National Center for Research Resources (RR12169, RR13642, and
RR00865), and by Dr. Gaser’s Bundesministerium für Bildung und Forschung grant (01EV0709a). Further support
was provided by grants from the Human Brain Project (P20-MHDA52176 and 5P01-EB001955) and the following
National Institutes: Biomedical Imaging and Bioengineering, Mental Health, Drug Abuse, Cancer, and Neurologic
Disease and Stroke. For generous support, we also thank the Brain Mapping Medical Research Organization, the
Robson Family, the Northstar Fund, and the following foundations: Brain Mapping Support, Pierson-Lovelace,
Ahmanson, Tamkin, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community,
Jennifer Jones-Simon, and Capital Group Companies.
Correspondence should be addressed to Dr. Arthur W. Toga, Laboratory of Neuro Imaging, Department of
Neurology, School of Medicine, University of California, Los Angeles, 635 Charles Young Drive South, Suite
225, Los Angeles, CA 90095-7334. E-mail: [email protected].
DOI:10.1523/JNEUROSCI.2261-09.2009
Copyright © 2009 Society for Neuroscience 0270-6474/09/2914265-06$15.00/0
controlled for individual differences in brain size, others did not.
Regardless of such corrections, it remains unclear whether the
observed larger measurements in female brains are characteristic
for women (i.e., attributable to biological sex per se), or whether
they are just typical for small brains (i.e., attributable to brain
size) (Leonard et al., 2008).
Evaluating men and women who have the same brain sizes
provides an invaluable opportunity to study the true contribution of biological sex on cerebral characteristics, independently of
brain size. Interestingly, only one previous study has analyzed a
subset of 18 female and 18 male subjects matched for age and
brain volume to confirm the presence of thicker cortices observed
in females than in males (Sowell et al., 2007). However, no details
concerning the age of subjects (the whole sample consisted of 176
healthy individuals between the ages of 7 and 87 years) or the
brain size matching procedures were provided. To our knowledge, no other study has compared cerebral features in equally
sized male and female brains. The sparseness of such analyses is
most likely attributable to the difficulty creating samples comprising men and women of similar brain size, as intracranial volumes of male and female brains differ on average by about 13–15%
(Gur et al., 1999; Luders et al., 2005; Leonard et al., 2008). Fortunately, the recent establishment of large-scale databases encompassing thousands of brain images now provides the opportunity
to select from a vast pool of subjects. In the present study we used
the International Consortium for Brain Mapping (ICBM) database (Mazziotta et al., 2009) to select a sample of 24 male and 24
female brains identical in size. In addition, we selected the 24
largest male brains and the 24 smallest female brains. Using this
set of brains (n ! 96), we analyzed regional volumes of GM to
Luders et al. • Larger Regional Gray Matter Volumes in Women
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Table 1. Age and total brain volume (TBV)
Matched sample (n ! 48)
Age
TBV
Extreme sample (n ! 48)
Men (n ! 24)
Women (n ! 24)
Men (n ! 24)
Women (n ! 24)
42.96 $ 12.31
1406.57 $ 101.69
43.88 $ 14.74
1406.62 $ 101.41
39.33 $ 14.79
1623.74 $ 68.94
45.75 $ 13.64
1221.58 $ 62.99
Age (mean $ SD) is shown in years; TBV (mean $ standard deviation) is shown in milliliters. Matched men and
matched women do not differ with respect to TBV. Extreme men consist of men with the largest TBVs; extreme
women consist of women with the smallest TBVs.
address whether brain size accounts for observed sex differences,
or whether anatomical differences between male and female
brains exist independently of brain size effects.
Materials and Methods
Subjects. Our initial sample included 153 healthy subjects (72 men and 81
women), ranging between 18 and 82 years, from the ICBM database of
normal adults (http://www.loni.ucla.edu/ICBM/). Subjects with any potential medical disorders that could affect brain structure or function as
well as subjects with brain-structural abnormalities in their MRI scans
had been excluded from this database (Mazziotta et al., 2009). To minimize the confounding effects of age-related brain atrophy on outcomes
of the present study, we additionally excluded all subjects who were older
than 70 years. The images of the remaining sample of 145 subjects (72
men and 73 women) were preprocessed as detailed below to calculate the
total brain volumes (TBVs). Based on the resulting TBVs, we created two
samples of subjects.
Sample I (hereafter referred to as “matched sample”) consisted of 48
subjects (24 men and 24 women) carefully matched for TBV. The maximum difference of TBV within a matched pair was 5.16 ml. Age ranged
between 19 and 69 years (men: 21– 61 years; women: 19 – 69 years). The
mean age of matched men and matched women did not differ significantly (for means and SDs, see Table 1). The matched sample included
five left-handers (two men; three women); handedness information was
obtained using the ICBM Demographic and Neurocognitive Inventory
(http://ric.uthscsa.edu:9000/icbm_dani/).
Sample II (hereafter referred to as “extreme sample”) also consisted of
48 subjects (24 men and 24 women) and represented the female subjects
with the smallest TBVs as well as the male subjects with the largest TBVs.
Of note, there was no overlap to subjects from the matched sample to
ensure independence of data in subsequent statistical analyses. Age
ranged between 18 and 69 years (men: 18 – 69 years; women: 19 – 65
years). The mean age of extreme men and extreme women did not differ
significantly. The matched sample included seven left-handers (four
men; three women). All subjects gave informed consent according to
institutional guidelines of the University of California, Los Angeles
(UCLA) Institutional Review Board.
Image acquisition. All brain images were acquired on the same site
(UCLA) and on the same scanner (a Siemens Sonata 1.5-T MRI system)
using a three-dimensional T1-weighted sequence (magnetizationprepared rapid-acquisition gradient echo) with the following parameters: repetition time ! 1900 ms; echo time ! 4.38 ms; flip angle ! 15°;
160 contiguous 1 mm sagittal slices; field of view ! 256 " 256 mm;
matrix size ! 256 " 256; voxel size ! 1.0 " 1.0 " 1.0 mm.
Preprocessing. Data were processed and examined using the SPM8
software (Wellcome Department of Imaging Neuroscience Group,
London, UK; http://www.fil.ion.ucl.ac.uk/spm) and the VBM8 toolbox (http://dbm.neuro.uni-jena.de/vbm.html). That is, within the same
generative model (Ashburner and Friston, 2005), images were corrected
for bias-field inhomogeneities, registered using linear (12-parameter affine) and nonlinear transformations, and tissue-classified into GM, white
matter (WM), and CSF. The segmentation procedure was further refined
by accounting for partial volume effects (Tohka et al., 2004), by applying
adaptive maximum a posteriori estimations (Rajapakse et al., 1997), and
by applying a hidden Markov random field model (Cuadra et al., 2005),
as described by Gaser (2009).
Total brain volume analysis. Using the tissue-classified partitions,
global tissue volumes were determined in milliliters by counting the
voxels representing GM, WM, and CSF in their native dimensions. TBV
was calculated by adding GM, WM, and CSF volumes and used as determinant to create the two main samples of this study (i.e., the matched
sample and the extreme sample), as described above. After establishing
the two main samples, male and female subgroups were compared with
respect to TBV. In addition, we calculated the brain size-adjusted global
tissue volumes (ratios) by dividing the GM, WM, and CSF volumes by
the TBV. We then compared these GM, WM, and CSF ratios between
matched men and matched women.
Regional gray matter volume analysis. The GM partitions were modulated to preserve actual GM values locally, while still accounting for
individual differences in brain size (via proportional scaling). For this
purpose, the normalized GM partitions were multiplied by the nonlinear
components (but not the linear components) derived from the normalization matrix. Finally, the modulated GM volumes were smoothed with
a Gaussian kernel of 12 mm full width at half maximum (FWHM). Using
these smoothed GM segments, we conducted the statistical analyses, as
outlined below.
We included the four groups consisting of the 24 matched men, the 24
matched women, the 24 extreme men (i.e., with the largest TBV), and the
24 extreme women (i.e., with the smallest TBV) into a 2 " 2 analysis of
covariance (ANCOVA) design, with age as nuisance variable. That is,
conducting voxelwise F tests, we estimated (1) the main effects of sex, (2)
the main effects of brain size, and (3) sex " brain size interactions, while
removing the variance associated with age. More specifically, the main
effect of sex was estimated by contrasting male subjects (i.e., matched
men and extreme men) against female subjects (i.e., matched women and
extreme women). The main effect of brain size was estimated by comparing subjects with larger brain sizes (i.e., matched women and extreme
men) against subjects with smaller brain sizes (i.e., matched men and
extreme women). To avoid possible edge effects between different tissue
types, all voxels with GM values of #0.1 were excluded (absolute threshold masking). Statistical outcomes were corrected for multiple comparisons using false discovery rate (FDR) at p ! 0.05. Significant findings
were restricted to clusters exceeding the expected numbers of voxels per
cluster (spatial extent threshold), calculated according to the theory of
Gaussian random fields. Significant main effects were followed up with
post hoc t tests to investigate the differences between male and female
subgroups. More specifically, we compared (1) extreme women and extreme men; (2) matched women and extreme men; (3) extreme women
and matched men; and (4) matched women and matched men. Although
post hoc tests were corrected for multiple comparisons using FDR at p !
0.05 with appropriate extent thresholds applied, we also generated a
series of maximum intensity projections without applying extent thresholds and not corrected for multiple comparisons at p ! 0.001. Of note,
only uncorrected outcomes allow for a direct comparability between
significance profiles of different comparisons because applying FDR corrections results in different T thresholds due to the adaptive behavior of
the FDR procedure (Nichols and Hayasaka, 2003).
Results
Total brain volumes
As expected, there were significant TBV differences between all
men (n ! 48) and all women (n ! 48), with larger volumes in
men ( p # 0.001). Table 1 shows the means and SDs for male and
female subsamples. As expected, there were no significant differences with respect to TBV between the matched men and the
matched women (there were also no significant differences with
respect to GM, WM, and CSF ratios).
There were significant differences between the extreme men
and the extreme women ( p # 0.001) with larger TBVs in men.
There were also significant differences between the extreme men
and the matched women ( p # 0.001), as well as between the
matched men and the extreme women ( p # 0.001), with larger
TBVs in men. The mean differences between men and women in
the latter two comparisons were similar (i.e., 217 and 185 ml,
Luders et al. • Larger Regional Gray Matter Volumes in Women
J. Neurosci., November 11, 2009 • 29(45):14265–14270 • 14267
respectively) and considerably smaller than when comparing
male and female extremes (402 ml).
Regional gray matter volumes
As illustrated in Figure 1a, for the comparisons of regional GM
volumes between all men and all women, we revealed significant
main effects of sex at p ! 0.05 (FDR-corrected) and restricting
outcomes to clusters exceeding k ! 1000 voxels (i.e., the calculated spatial extent threshold according to the theory of Gaussian
random fields). There were no significant effects of brain size and
no significant interactions between sex and brain size.
When conducting post hoc tests, there were no regions of
larger GM volumes in men than in women at p ! 0.001 (uncorrected), regardless of which subgroups were compared with each
other. In contrast, we revealed a number of regions where women
had larger GM volumes than men at p ! 0.001 (uncorrected).
These sex effects (women % men) decreased slightly when brain
size differences between men and women declined (Fig. 1b– e).
Importantly, we also revealed clusters of significantly larger GM
volumes in women than in men in all four comparisons when
applying FDR corrections at p ! 0.05 and restricting outcomes to
clusters exceeding k ! 1000 voxels.
Figure 2 provides the detailed T statistics associated with the
specific comparison within the matched sample at p ! 0.05
(FDR-corrected) and k ! 1000. As illustrated, we revealed significantly larger GM volumes in women than in men in the following three main clusters: cluster 1 (k ! 6505) consisted of the left
and right caudate (extending into other regions of the basal ganglia as well as into the left orbitofrontal region). Cluster 2 (k !
2224) comprised regions of the left superior temporal gyrus, and
cluster 3 (k ! 1982) encompassed regions of the left superior
frontal gyrus (for MNI coordinates pertaining to cluster-specific
local maxima, refer to Fig. 2).
Exploratory analyses
Although there was a lack of clusters indicating a significant main
effect of brain size (or interactions between brain size and sex), we
conducted further exploratory analyses to investigate possible
trends when comparing small and large brains within males only
(i.e., matched vs extreme men; mean difference: 217 ml) and also
separately within females only (i.e., extreme vs matched women;
mean difference: 185 ml). For this purpose we abstained from
applying corrections for multiple comparisons. However, none
of these comparisons revealed any significant clusters at p !
0.001, uncorrected.
Discussion
Brain size effects versus sex effects
The main goal of this study was to determine whether brain size
accounts for what appear to be sex differences, or whether the
observed anatomical differences between male and female brains
exist independently of brain size effects. During the first step of
the statistical analysis (F tests), we observed that there was a significant main effect of sex (but no main effect of brain size and no
interaction between the two). However, both sex and brain size
effects might have contributed to the main effects of sex, because
all men and all women, together, differed significantly with respect to TBV. Thus, we conducted post hoc comparisons (t tests)
between matched men and matched women, who did not differ
with respect to TBV. Any significance clusters would indicate
pure sex effects independent of brain size. Indeed, we revealed a
number of regions where matched women had significantly
larger GM volumes than in matched men, suggesting that ana-
Figure 1. Sex differences in regional GM (main effect and subsamples). Displayed are maximum intensity projections superimposed onto the SPM standard glass brain template (sagittal
and coronal view). a illustrates the main effect of sex (bidirectional). Statistical outcomes are
corrected for multiple comparisons using FDR at p ! 0.05. Shown are clusters exceeding a
spatial extent threshold of 1000 voxels, which corresponds to the expected numbers of voxels
per cluster. b– e illustrate the outcomes of the subsequent post hoc tests, where women have
larger regional GM volumes than men (women % men). The illustrated spatial profiles are
significant at p ! 0.001 (uncorrected) without applying cluster extent thresholds.
14268 • J. Neurosci., November 11, 2009 • 29(45):14265–14270
Luders et al. • Larger Regional Gray Matter Volumes in Women
Figure 2. Sex differences in regional GM (matched sample). Displayed are section views of the single subject SPM standard brain. The clusters indicate brain regions where the matched women
had significantly larger GM volumes than the matched men. The color intensity represents t-statistic values at the voxel level. Statistical outcomes are corrected for multiple comparisons using FDR
at p ! 0.05. Shown are clusters exceeding a spatial extent threshold of 1000 voxels and the respective cluster-specific local maxima (see crosshairs), including their MNI coordinates. The results are
presented in neurological convention (right is right).
tomical differences between male and female brains exist independently of brain size effects.
In addition, we conducted post hoc analyses (t tests) comparing men and women whose TBVs differed at various degrees. If
brain size had a significant impact on regional GM volumes, then
observed sex effects should change drastically depending on the
degree to which male and female groups differed with respect to
TBV. Interestingly, sex effects became less pronounced the more
male and female TBVs resembled each other (Fig. 1b– e). However, differences between profiles were rather small. Together
with the lack of significant brain size effects (F tests) as well as the
lack of significant differences between small and large brains
within males and within females (exploratory analyses), our study
seems to indicate that brain size effects on observed sex differences are negligible. These findings and conclusions corroborate
implications from the one existing study comparing a subset of 18
males and 18 females matched for brain size (Sowell et al., 2007).
Sowell and colleagues revealed a larger cortical thickness in females in several brain regions and reported that “the pattern of
results in the subset of matched subjects is similar to that observed in the whole group.”
While these outcomes appear to disagree with previous findings indicating that brain volume (rather than sex) is the main
variable accounting for differences in GM proportion (Lüders et al.,
2002; Leonard et al., 2008), they are not contradicting but complementary if brain size effects account for global tissue volumes (and
the size of selected predefined structures), while sex effects account
for regional GM (and regional cortical thickness). In strong agreement with this assumption, we detected significant differences between matched men and matched women with respect to regional
GM, but not with respect to global tissue ratios.
Spatial location of sex effects
While we did not detect any regions of larger GM volume in men
than in women, there were a number of regions indicating larger
GM volumes in women than in men. We will comment on significance clusters detected when comparing matched women and
matched men in particular. This constitutes the special case of
this study, where possible effects of brain size can be excluded
with certainty. As detailed below, there is a strong resemblance
between current findings and outcomes from previous studies
(i.e., where men always exhibited larger brains than women). Of
note, brain size matching is not proposed to substitute traditional
analyses that include men and women with different brain sizes.
Such analyses will continue to provide important clues about
differences between male and female brains, especially if appropriate strategies are used to account for individual differences in
brain size. However, brain size matching, as applied in the present
study, clarifies whether observed sex differences are attributable
to brain size or to biological sex per se.
Comparing men and women with identical brain sizes, we
detected the largest clusters in the right and left caudate extending
into adjacent regions of the basal ganglia, as well as into the left
orbitofrontal region (cluster 1). Larger GM volumes in the female
caudate agree with findings by Good et al. (2001), who detected
an increased GM concentration in females compared with males
adjacent to the caudate heads; they also corroborate observations
by Giedd et al. (1996) and Filipek et al. (1994), who reported
increased relative caudate volumes in females compared with
males. In addition, increased GM volumes in the female left orbitofrontal region seems to confirm outcomes from the above
mentioned study by Good et al. (2001), who reported increased
GM volumes in females in the inferior frontal gyri (however, the
Luders et al. • Larger Regional Gray Matter Volumes in Women
exact spatial correspondence with our findings cannot be established, as figures and coordinates were not provided). Furthermore, the findings of larger left orbitofrontal GM volumes in
women resemble findings of thicker cortices in this particular
region in female brains (Luders et al., 2006a).
The other two main clusters detected in the current study were
located in the left superior temporal gyrus (cluster 2) and the left
superior frontal gyrus (cluster 3). Interestingly, both of these regions have been previously reported to show 12.8% (superior
temporal gyrus) and 23.2% (dorsolateral prefrontal cortex)
greater GM percentages (corrected for overall brain size and age)
in females than in males (Schlaepfer et al., 1995). Similar findings
come from other studies where the brain size-adjusted volumes
of the superior frontal cortex as well as its GM concentration were
found to be larger in females than in males (Goldstein et al., 2001;
Luders et al., 2006a). In addition, the volume of the superior
temporal cortex (expressed as a proportion of total cerebral volume) was reported to be 17.8% larger in females than in males
(Harasty et al., 1997). In further agreement with current outcomes, the brain size-adjusted volumes of the primary auditory
cortex were found to be significantly larger in women than in
men (Rademacher et al., 2001). Moreover, GM volumes as well as
GM concentration, and cortical thickness measures were observed to be larger in females in the banks of the left superior
temporal sulcus (Good et al., 2001), within Wernicke’s area
(Luders et al., 2005), and across large parts of the superior temporal gyrus (Luders et al., 2006a). Importantly, Sowell and colleagues who analyzed males and females, matched for brain size,
also observed the left superior temporal gyrus to be one of the
regions, where females had significantly thicker cortices than
males (Sowell et al., 2007).
Possible functional implications and further considerations
Regional GM is a composite measure of different microunits,
such as neuronal bodies, axons, dendrites, synapses, glia cells, and
others. Given that MRI signal strength is somewhat related to
cellular characteristics, it is tempting to immediately relate the
larger female GM volumes to specific cognitive functions (i.e., in
which women show better performance). For example, if a larger
regional GM volume reflects more numerous neurons, such tissue enlargements might be advantageous by facilitating an efficient processing of ingoing and outgoing information, which
might be beneficial for cognitive performances. In support of this
assumption, histological data has shown regionally increased female neuronal densities in the posterior temporal cortex (Witelson
et al., 1995) and greater dendritic values in Wernicke’s area
(Jacobs et al., 1993). This seems to agree with our findings of
increased GM concentration in the left posterior superior
temporal gyrus. Given that parts of the superior temporal gyrus are involved in language processing, one could speculate
that the observed larger GM volumes in females are associated
with women’s superior language skills (Kimura, 1999). However, further studies characterizing the relationship between
cerebral microstructure, observable differences in brain anatomy, and brain function is clearly necessary before we can
precisely interpret the regional sex differences. Regardless their
functional relevance, we suggest that the observed increased regional GM volumes in female brains constitute sex-dependent
redistributions of tissue volume (rather than individual adjustments to brain size). Future research needs to resolve the exact
underlying mechanisms (e.g., neurogenesis, synaptogenesis, apoptosis, and/or synaptic pruning), the precise nature of their determinants (e.g., direct genetic versus hormonal effects), as well
J. Neurosci., November 11, 2009 • 29(45):14265–14270 • 14269
as their possible evolutionary relevance (e.g., sex-dependent selection for certain skills).
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